CIS controls the functional polarization of GM-CSF-derived macrophages

• Published in: Cellular & molecular immunology 2023-01, Vol.20 (1), p.65-79
• Main Authors: Zhang, Shengbo, Rautela, Jai, Bediaga, Naiara G., Kolesnik, Tatiana B., You, Yue, Nie, Junli, Dagley, Laura F., Bedo, Justin, Wang, Hanqing, Sun, Li, Sutherland, Robyn, Surgenor, Elliot, Iannarella, Nadia, Allan, Rhys, Souza-Fonseca-Guimaraes, Fernando, Xie, Yi, Wang, Qike, Zhang, Yuxia, Xu, Yuekang, Nutt, Stephen L., Lew, Andrew M., Huntington, Nicholas D., Nicholson, Sandra E., Chopin, Michaël, Zhan, Yifan
• Format: Article
• Language: English
• Subjects: 631/250/38; 631/80/86; Antibodies; Asthma; Biomedical and Life Sciences; Biomedicine; Cell Differentiation; Colony-stimulating factor; Cytokines; Cytokines - metabolism; Granulocyte-macrophage colony-stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Hypersensitivity; Immune response; Immunology; Inflammation; Interferon regulatory factor; Interferon Regulatory Factors - metabolism; Leukocytes (granulocytic); Lymphocytes T; Macrophages; Medical Microbiology; Microbiology; Monocytes; Monocytes - metabolism; Polarization; Signal transduction; Stat5 protein; Vaccine
• ISSN: 2042-0226; 1672-7681; 2042-0226
• DOI: 10.1038/s41423-022-00957-z

The cytokine granulocyte-macrophage-colony stimulating factor (GM-CSF) possesses the capacity to differentiate monocytes into macrophages (MØs) with opposing functions, namely, proinflammatory M1-like MØs and immunosuppressive M2-like MØs. Despite the importance of these opposing biological outcomes, the intrinsic mechanism that regulates the functional polarization of MØs under GM-CSF signaling remains elusive. Here, we showed that GM-CSF-induced MØ polarization resulted in the expression of cytokine-inducible SH2-containing protein (CIS) and that CIS deficiency skewed the differentiation of monocytes toward immunosuppressive M2-like MØs. CIS deficiency resulted in hyperactivation of the JAK-STAT5 signaling pathway, consequently promoting downregulation of the transcription factor Interferon Regulatory Factor 8 (IRF8). Loss- and gain-of-function approaches highlighted IRF8 as a critical regulator of the M1-like polarization program. In vivo, CIS deficiency induced the differentiation of M2-like macrophages, which promoted strong Th2 immune responses characterized by the development of severe experimental asthma. Collectively, our results reveal a CIS-modulated mechanism that clarifies the opposing actions of GM-CSF in MØ differentiation and uncovers the role of GM-CSF in controlling allergic inflammation.